Low cost test strip and method to measure analyte

ABSTRACT

Materials and manufacturing techniques to produce test strips in high volume at low-cost for the measurement of gas in various industries and environments are disclosed. The test strip is generally comprised of a substrate, at least one electrical connection, at least one sensing chemistry and at least one additional layer. The test strip may provide a quantitative author a qualitative read out. A method for collecting and analyzing data to monitor and manage patients with chronic respiratory disease is disclosed. Implementations include software applications, connected medical devices, web servers and electronic catalogs. A method for identifying treatment trends from a population combining medical, biological and environmental data is disclosed. A method for proactively alerting and patients, caregivers and medical providers to trends in health by using the implementations of the invention are disclosed.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application claims the benefit under 35 U.S.C. § 119(e) to UnitedStates Provisional Patent Application No. 62/146,824, entitled Low CostTest Strip and Method to Measure Analyte, filed Apr. 13, 2015, U.S.Provisional Patent Application No. 62/013,233, entitled Method firCollecting and Analyzing Data to Monitor and Manage Patients withChronic Respiratory Disease, filed Jun. 17, 2014, U.S. ProvisionalPatent Application No. 62/009,531, entitled Low Cost Test Strip AndMethod to Measure Analyte, filed Jun. 9, 2014, which are herebyincorporated by reference in their entirety.

BACKGROUND Field of Invention

This invention relates to a gas sensing system that includes a low-costlimited-use test strip configured to measure gas, a system fordelivering gas to the test strip and a device for controlling andreading the output of the test strip. In other aspects, the invention isgenerally related to the diagnosis and monitoring of therapy forpatients with chronic respiratory disease such as asthma and chronicobstructive pulmonary disease.

Description of Related Art

There are many different types of sensors and technologies available forgas and analyte detection known in the art. In the human medicalindustry, gas sensors are used in many areas including anesthesia andrespiratory care. The sensors are typically configured to monitorinhaled anesthetic agents, O₂, CO₂, and N₂O. Other examples include,measuring nitric oxide in exhaled breath, which has recently gainedtraction to diagnosis and monitor airway inflammation in patients withchronic respiratory diseases. In order to measure nitric oxide at aclinically relevant value, the sensing technology must be capable ofdetecting limits as low as 1-300 parts per billion. Two technologies arecommercially available today for detecting nitric oxide in exhaledbreath. The first measures chemiluminescence whereby the breath sampleis mixed with ozone and a luminescent signal is monitored afterexcitation with incident light. The second available technology uses anelectrochemical signal, typically via cyclic voltammetry. The mechanicsof chemiluminescence and electrochemical sensing are known in the art.

Both technologies have the disadvantage of being complicated and havinghigh costs associated with the sensor itself, as well as the system todeliver gas to the sensor and provide an accurate reading. Currentchemiluminescence and electrochemical sensing technologies requirecomplex systems to accurately measure nitric oxide in breath. Forexample, sensing by chemiluminescence requires an ozone generator,vacuum pump, filters, microprocessor, power supply, photodetector, etc.These items are housed in a device the size of a desktop computer andcan cost tens of thousands of dollars. Electrochemical sensors,likewise, require very sensitive electronics, hermetically sealedanalysis chambers, and complicated signal processing. Moreover,electrochemical sensors require an assembly process not suitable forhigh volume, low-cost production. Likewise, electrochemical sensors andthe systems to process the signal may cost thousands of dollars.

Both technologies have further disadvantage by being cumbersome and notfriendly to the user (e.g. patient, technician, medical provider etc.)

Chronic respiratory diseases, such as Asthma and COPD, are diseasescharacterized by chronic underlying inflammation, airwayhyperresponsiveness and sudden obstruction and constriction. The goal ofcare is to achieve and maintain control. Control of the disease meansreduce frequency and intensity of symptoms and the risk of futureattacks. To achieve and maintain control, physicians must selectmedications from approximately nine classes of drugs. Each drug classconsists of multiple drugs each with a different active ingredient. Inmost patients, multiple drugs from multiple classes are used incombination. In addition to a variety of choice, the physician mustselect the most appropriate dose and frequency of use.

Achieving and maintaining control is difficult for physicians becausepatient's response and adherence to therapy is highly variable.Physicians rely heavily on information provided by the patients inbetween visits relating to the frequency and intensity of theirsymptoms. This information is used to guide physicians' decisions onchoosing the appropriate medication. The effectiveness and adherence totherapy is unknown until a follow up visit that can occur because of anemergency or be schedule weeks or months in the future.

The variability of the disease, tools available and subjective data frompatients makes achieving and maintaining control extremely difficult.The result is a disease that is poorly managed and yields a massiveconsumption of resources in the form of physician office visits,emergency room use, hospital inpatient visits, prescription medicationsand missed days of work or school. There is a need for a better way tomonitor, manage and treat patients with chronic respiratory diseases.

BRIEF SUMMARY OF THE INVENTION

One aspect of the invention involves a low cost test strip and methodsto measure an analyte.

In another aspect the invention, a system for determining theconcentration of at least one analyte in a fluid sample is disclosed, inwhich the system comprises a base substrate, a first electrode pairdisposed over the substrate, a second electrode pair disposed over thesubstrate, an active sensing chemistry responsive to the analyte in thesample and in electrical communication with the first electrode pair, areference sensing chemistry responsive to the analyte in the sample andin electrical communication with the second electrode pair, and ablocking layer disposed over the reference sensing chemistry, theblocking layer for inhibiting contact between the reference sensingchemistry and at least one analyte in the fluid sample. In anotherembodiment, the system further comprises a membrane layer disposed overthe sensing chemistry. In another embodiment the system of furthercomprises a protective layer defining a window disposed above themembrane layer.

In another embodiment of the system a first electrode in the firstelectrode pair is in electrical communication with the active sensingchemistry, a first electrode in the second electrode pair is inelectrical communication with the reference sensing chemistry, and asecond electrode is electrical communication with both the activesensing chemistry and the reference sensing chemistry, the secondelectrode forming the second electrode of both the first and the secondelectrode pairs. In another embodiment of the system at least a portionof the membrane layer is disposed over the blocking layer. In anotherembodiment of the system the membrane layer is selectively permeable toat least one analyte in the fluid sample. In some embodiments of thesystem the electrodes comprise carbon. In some embodiments of the systemthe electrodes comprise silver. In some embodiments of the system theelectrodes comprise gold.

In some embodiments the system further comprises a dielectric layerdisposed over at least a portion of the electrodes. In some embodimentsof the system the space between the electrodes that is bridged by thesensing chemistry is less than or equal to 2.5 millimeters.

In some embodiments of the system at least one of the active sensingchemistry and the reference sensing chemistry comprise an organicmolecule having at least one ionic functional group. In some embodimentsof the system at least one of the active sensing chemistry and thereference sensing chemistry comprise an organic dye. In otherembodiments of the system at least one of the active sensing chemistryand the reference sensing chemistry comprise an aromatic compound. Inother embodiments of the system at least one of the active sensingchemistry and the reference sensing chemistry comprise a metal-ligandcomplex. In other embodiments of the system at least one of the activesensing chemistry and the reference sensing chemistry comprise a metaloxide. In other embodiments of the system at least one of the activesensing chemistry and the reference sensing chemistry comprise a metal.In other embodiments of the system at least one of the active sensingchemistry and the reference sensing chemistry comprise a metal salt. Inother embodiments of the system at least one of the active sensingchemistry and the reference sensing chemistry comprise a nanostructure.In other embodiments of the system at least one of active sensingchemistry and the reference sensing chemistry comprise a polymer. Insome embodiments of the system the active sensing chemistry and thereference sensing chemistry comprise the same material.

In some embodiments of the system at least one of the active sensingchemistry and the reference sensing chemistry comprise a heterocyclicmacrocycle. In some embodiments of the system the heterocyclicmacrocycle is a porphyrin.

In some embodiments of the system a volume of active sensing chemistrydisposed on the substrate is less than or equal to 1 milliliter ofmaterial. In some embodiments of the system of claim 1, wherein a volumeof reference sensing chemistry disposed on the substrate is less than orequal to 1 milliliter of material.

In some embodiments of the system the active sensing chemistry and thereference sensing chemistry are responsive to at least one same analytein the sample. In some embodiments of the system the blocking layerdisposed over the reference sensing chemistry is substantiallyimpermeable to an analyte of interest in the fluid sample. In someembodiments of the system the blocking layer disposed over the referencesensing chemistry defines a window to expose the active sensingchemistry to the fluid sample. In some embodiments of the system theblocking layer disposed over the reference sensing chemistry comprisesan adhesive. In some embodiments the adhesive is a pressure sensitiveadhesive. In some embodiments of the system the adhesive is a heatactivated adhesive.

In some embodiments of the system the membrane layer comprises at leastone of porous polymers, non-porous polymers, composite materials,fibrous materials, woven textiles, non-woven textiles, polymers,adhesives, films, and gels. In some embodiments of the system themembrane layer comprises PTFE. In other embodiments of the system themembrane layer comprises silicone. In some embodiments of the system asilicone transfer layer attaches the membrane layer to at least oneother layer. In some embodiments of the system the active sensingchemistry and the reference sensing chemistry are disposed on a teststrip.

In another embodiments the system further comprises a circuit incooperation with the active sensing chemistry and the reference sensingchemistry to form a bridge circuit. In some embodiments the system thesystem further comprises a meter configured to deliver at least aportion of the fluid sample to at least the sensing chemistry. In someembodiments of the system at least a portion of the meter in contactwith the fluid sample comprises stainless steel. In some embodiments ofthe system at least a portion of the meter in contact with the fluidsample comprises aluminum. In some embodiments of the system rein atleast a portion of the meter in contact with the fluid sample comprisessiliconized materials. In some embodiments of the system at least aportion of the meter in contact with the fluid sample comprises glass.In some embodiments of the system at least a portion of the meter incontact with the fluid sample comprises Teflon. In some embodiments ofthe system at least a portion of the meter in contact with the fluidsample comprises a Teflon-coated material. In some embodiments of thesystem at least a portion of the meter in contact with the fluid samplecomprises a plastic. In some embodiments of the system at least aportion of the meter in contact with the fluid sample comprises K-resin.

In some embodiments of the system the meter is configured to accept afluid sample from a human user. In some embodiments of the system thefluid sample is exhaled breath from the human user. In some embodimentsof the system the meter is configured to apply the fluid sample to thetest strip at a flow rate that is less than or equal to a flow rate forthe exhaled breath. In some embodiments of the system the flow rate isless than or equal to 3000 standard cubic centimeters per minute. Insome embodiments of the system the flow rate is less than or equal to500 standard cubic centimeters per minute. In some embodiments of thesystem the flow rate is less than or equal to 350 standard cubiccentimeters per minute. In some embodiments of the system the flow rateis less than or equal to a peak expiratory flow of a representativehuman.

In some embodiments of the system the meter is configured to accept asample volume that is less than or equal to a forced vital capacity of arepresentative human. In some embodiments of the system he meter isconfigured to divert only a portion of the exhaled breath sample to thesensing chemistry. In some embodiments of the system the meter isconfigured to divert only a last 3 seconds of the exhaled breath. Insome embodiments of the system the exhaled breath sample is 10 secondsin duration. In some embodiments of the system the meter is configuredto control a flow rate of the fluid sample. In some embodiments of thesystem the meter is configured to control the flow rate of the fluidsample to about 2700 standard cubic centimeters per minute to about 3300standard cubic centimeters per minute. In some embodiments of the systemthe meter is configured to control the flow rate of the fluid sample toabout 2850 standard cubic centimeters per minute to about 3150 standardcubic centimeters per minute. In some embodiments of the system themeter is configured to positively restrict a pressure of the fluidsample. In some embodiments of the system the meter is configured topositively restrict the pressure from about 5 centimeters of watercolumn to about 20 centimeters of water column.

In some embodiments the system further comprises a filter to remove atleast one selected analyte from the fluid sample. In some embodimentsthe system further comprises a filter to remove at least one selectedanalyte from the fluid sample prior to the fluid sample contacting theactive sensing chemistry. In some embodiments the selected analyte isnitric oxide. In some embodiments the selected analyte is nitrogendioxide.

In some embodiments the system further comprises a meter configured toprovide an output correlating to an analyte concentration. In someembodiments the system further comprises a meter configured to providefeedback regarding an input flow rate of the fluid sample. In someembodiments the feedback is visual. In some embodiments the meterfurther comprises a display that provides the visual feedback. In someembodiments the feedback is audio. In some embodiments feedback isresistance to the input flow of the fluid sample.

In some embodiments the system further comprises a chamber, the sensingchemistry being disposed within the chamber. In some embodiments of thesystem the chamber is configured to create turbulent flow. In someembodiments of the system the chamber is configured to direct theturbulent flow at the sensing chemistry. In some embodiments of thesystem in the chamber has an entrance path for the fluid sample. In someembodiments of the system the chamber has an exit path for the fluidsample. In some embodiments of the system the active chemistry andsensing chemistry are pre-mixed before deposition on the substrate. Insome embodiments of the system the active and sensing chemistry aredeposited in less than or equal to four steps.

Another aspect of the invention includes a method for determining aconcentration of at least one analyte in a fluid sample, comprising,providing a system for determining the concentration of the at least oneanalyte in the fluid sample, the system comprising a base substrate, afirst electrode pair disposed over the substrate, a second electrodepair disposed over the substrate, an active sensing chemistry responsiveto the analyte in the sample and in electrical communication with thefirst electrode pair, a reference sensing chemistry responsive to theanalyte in the sample and in electrical communication with the secondelectrode pair, a blocking layer disposed over the reference sensingchemistry, the blocking layer for inhibiting contact between thereference sensing chemistry and at least one analyte in the fluidsample, measuring at least one of a voltage across the first electrodepair, a resistance across the first electrode pair, and a current flowacross the first electrode pair, and measuring at least one of a voltageacross the second electrode pair, a resistance across the secondelectrode pair, and a current flow across the second electrode pair. Insome embodiments the method the system further comprises a membranelayer disposed over the sensing chemistry.

In some embodiments the method further comprises placing the system inthe path of the sample fluid. In some embodiments the fluid sample is abiological fluid. In some embodiments the fluid sample is exhaledbreath.

In some embodiment the method comprises a meter. In some embodiments ofthe method the meter provides an output. In some embodiments of themethod the output is based on at least one of (i) the measuring the atleast one of the voltage across the first electrode pair, the resistanceacross the first electrode pair, and the current flow across the firstelectrode pair and (ii) the measuring the at least one of the voltageacross the second electrode pair, the resistance across the secondelectrode pair, and the current flow across the second electrode pair.In some embodiments of the method the output is qualitative. In someembodiments of the method the output is quantitative.

In some embodiments the method comprising determining the analyteconcentration based on at least one of (i) the measuring the at leastone of the voltage across the first electrode pair, the resistanceacross the first electrode pair, and the current flow across the firstelectrode pair and (ii) the measuring the at least one of the voltageacross the second electrode pair, the resistance across the secondelectrode pair, and the current flow across the second electrode pair.In some embodiments the method further comprised determining the analyteconcentration based on performing the measurement steps more than once.

In some embodiments the method further comprises determining a change inat least one of the voltage across the first electrode pair, theresistance across the first electrode pair, the current flow across thefirst electrode pair, the voltage across the second electrode pair, theresistance across the second electrode pair, and the current flow acrossthe second electrode pair. In some embodiments the method furthercomprises, determining a first baseline measurement of at least one of afirst baseline voltage across the first electrode pair, a first baselineresistance across the first electrode pair, and a first baseline currentflow across the first electrode pair, and determining a second baselinemeasurement of at least one of a second baseline voltage across thesecond electrode pair, a second baseline resistance across the secondelectrode pair, and a second baseline current flow across the secondelectrode pair. In some embodiments the method further comprisesdetermining a change in at least one of the voltage across the firstelectrode pair relative to the first baseline voltage, the resistanceacross the first electrode pair relative to the first baselineresistance, the current flow across the first electrode pair relative tothe first baseline current flow, the voltage across the second electrodepair relative to the second baseline voltage, the resistance across thesecond electrode pair relative to the second baseline resistance, andthe current flow across the second electrode pair relative to the secondbaseline current flow.

In some embodiments of the method a user of the system takes multiplemeasurements over the course of several hours. In some embodiments ofthe method a user of the system takes multiple measurements over thecourse of at least one of more than one day, week, month, or year. Insome embodiments of the method the measuring steps take place over lessthan 1 day. In some embodiments of the method the measuring steps takeplace between 30 and 60 minutes. In some embodiments of the method themeasuring steps take place between 10 and 30 minutes. In someembodiments of the method the measuring steps take place between 1 and10 minutes. In some embodiments of the method the measuring steps takeplace in less than or equal to about 1 minute. In some embodiments ofthe method the measuring steps take place in less than or equal to about30 seconds. In some embodiments of the method the measuring steps takeplace in less than or equal to about 10 seconds. In some embodiments ofthe method the measuring steps take place in less than or equal to about3 seconds.

In some embodiments the method further comprises determining aconcentration range among a plurality of analyte concentration ranges inwhich the concentration of the at least one analyte falls based on atleast one of (i) the measuring the at least one of the voltage acrossthe first electrode pair, the resistance across the first electrodepair, and the current flow across the first electrode pair and (ii) themeasuring the at least one of the voltage across the second electrodepair, the resistance across the second electrode pair, and the currentflow across the second electrode pair. In some embodiments the methodfurther comprising displaying as output the analyte concentration rangedetermination. In some embodiments of the method the plurality ofconcentration ranges is dependent on an age of a patient providing thefluid sample. In some embodiments of the method when the age of thepatient is less than 12 years old, the plurality of analyteconcentrations ranges include: less than 20 parts per billion of theanalyte, between 20 and 35 parts per billion of the analyte, and greaterthan 35 parts per billion of the analyte. In other embodiments of themethod of claim 105, when the age of the patient great than or equal to12 years old, the plurality of analyte concentrations ranges include:less than 25 parts per billion of the analyte, between 25 and 50 partsper billion of the analyte, and greater than 50 parts per billion of theanalyte.

In some embodiments of the method the analyte is nitric oxide. In someembodiments of the method the plurality of analyte concentration rangesinclude a first range below a specified analyte concentration and asecond range above the specified analyte concentration.

In some embodiments of the method the specified analyte concentration isselected from a range of concentrations between 1 and 50 parts perbillion. In some embodiments the analyte is nitric oxide.

In some embodiments of the method the specified analyte concentration is20 parts per billion. In some embodiments of the method the analyte isnitric oxide.

In some embodiments of the method the specified analyte concentration is25 parts per billion. In some embodiments of the method the analyte isnitric oxide.

In some embodiments of the method the specified analyte concentration is35 parts per billion. In some embodiments of the method the analyte isnitric oxide.

In some embodiments of the method the specified analyte concentration is40 parts per billion. In some embodiments of the method the analyte isnitric oxide.

In some embodiments of the method the specified analyte concentration is50 parts per billion. In some embodiments of the method the analyte isnitric oxide.

In some embodiments of the method the specified analyte concentration is15 parts per million. In some embodiments of the method the analyte ismethane.

In some embodiments of the method the specified analyte concentration is20 parts per million. In some embodiments of the method the analyte ishydrogen.

In some embodiments the method further comprises providing the fluidsample. In some embodiments of the method at least one analyte is a gas.In some embodiments of the method the at least one analyte is nitricoxide. In some embodiments of the method the at least one analyte ishydrogen. In some embodiments of the method the at least one analyte ismethane. In some embodiments of the method the at least one analyteincludes hydrogen and methane. In some embodiments of the method the atleast one analyte is present in a biological fluid. In some embodimentsof the method the biological fluid is exhaled breath. In someembodiments of the method the at least one analyte is nitric oxide. Insome embodiments of the method the at least one analyte is hydrogen. Insome embodiments of the method the at least one analyte is methane. Insome embodiments of the method the at least one analyte includeshydrogen and methane.

In some embodiments of the method the active sensing chemistry and thereference sensing chemistry are disposed on a test strip. In someembodiments of the method the test strip is configured to be for singleuse. In some embodiments of the method the test strip is configured tobe for multiple uses. In some embodiments of the method the test stripis configured to be for a specified number of uses. In some embodimentsof the method the test strip is configured to be for less than or equalto three uses.

BRIEF DESCRIPTION OF FIGURES

In the drawings.

FIG. 1 is an example of one embodiment of the invention in a largersystem for monitoring patients.

FIG. 2 is an example of the assembled device and test strip ready foruse by a patient.

FIG. 3 is an example of variations of the assembled device, test stripand electronic reader.

FIG. 4a and FIG. 4b demonstrate examples of variations of the electronicsystems to provide a read out from the test strip.

FIG. 5a-5c demonstrate examples of variations of the mechanisms tocontrol the flow of gas to the test strip and methods of filtering thegas stream.

FIG. 6a demonstrates an example of the test strip incorporated into avessel.

FIG. 6b demonstrates an example of a vessel connecting to a reader.

FIG. 7 demonstrates various orientations of the test strip within thedevice.

FIG. 8 is an example of the devices configured to peel or pierce aprotective layer from the test strip.

FIG. 9a-b shows various configurations of electrodes and chemistries ona test strip.

FIG. 9c shows examples of test strips with integrated heaters, sensorsand electrical components.

FIG. 10 is an example of the sensing chemistry additives.

FIGS. 11 and 11 a show examples of a test strip with multiple layers.

FIG. 12 shows examples of fully assembled test strips.

FIG. 13a , FIG. 13b and FIG. 13c demonstrate an example of the teststrips in mass production.

FIG. 14 is provides examples of coating techniques for the test strip.

FIG. 15 demonstrates an example of diverting a portion of the exhaledbreath to the sensor.

FIG. 16 demonstrates an example of diverting a portion of the exhaledbreath to the sensor after inhaling through a filter.

FIG. 17 demonstrates an embodiment of the device that folds.

FIG. 17a demonstrates an embodiment of a device that folds andincorporates the design described in FIG. 15 and/or FIG. 16.

FIG. 17b demonstrates one embodiment of the invention wherein the readerand gas conditioning system are incorporated into a device.

FIG. 17c demonstrates an embodiment of the invention wherein the outputof the device is selected from a plurality of endpoints.

FIG. 18 depicts certain embodiments of a questionnaire.

FIG. 19 illustrates an example of combining like data from multiplepatients, sending the data to the cloud for analysis and generatingmeaningful information for multiple parties such as: payers, providers,patients and industry i.e. pharmaceutical and medical device companies.

FIG. 20 depicts certain embodiments of a mobile application thatcollects data in various forms and at various locations from a singlepatient. The data is sent to the cloud for storage and analysis.

FIG. 21 depicts certain embodiments of a medical professional monitoringthe data collected from patients.

FIG. 22 depicts certain embodiments of a software monitoring system toproactively alert patients, medical professionals and/or caregivers oftrend changes in health status.

DETAILED DESCRIPTION

The invention relates to the field of gas detection and may beconfigured in a variety of ways based on the gas of interest andenvironment in which the test strip is placed. At the most basic level,the test strip comprises a substrate and a sensing chemistry. In someembodiments, the test strip is generally comprised of a substrate, atleast one electrical connection, at least one sensing chemistry and atleast one additional layer. The layer, or layers, may serve a singlepurpose, or multiple purposes, for example, to protect the sensingchemistry from interfering substances, in addition to providing, forexample, a spacer between layers. The combination of layers may provideselective permeation of gases to the sensing chemistry. The test stripmay provide a quantitative and/or a qualitative read out. The test stripmay stand alone or be combined with other devices. Examples of thesedevices include, but are not limited to, mechanisms to control the gasflow, electronic means to power the device and provide a read out,temperature measurement and control, and/or mechanisms to filter the gasprior to readout.

One embodiment of the invention is for use in the medical industry. Itcomprises a test strip and device(s) configured to measure exhalednitric oxide in human breath. The information from the test strip anddevice may be part of a larger monitoring system for patient health. Thetest strip consists of a substrate, zero or more electrodes, at leastone sensing chemistry, and at least one layer to provide protectionagainst interfering substances. The test strip is in communication witha device to provide a signal and readout, and to control the flow of gasto the sensor.

One embodiment of the invention is a software application that combinesbiological, medical history and prescribed therapy, environmental andsymptom data from individual patients. This data is sent to a remoteserver where it is stored and combined with like data from otherpatients. The population data is analyzed and organized to create healthmanagement tools for healthcare providers, payers, patients andindustry.

Specific examples of the collected data may include but are not limitedto: biological data in the form of biomarkers such as scrum periostin,exhaled nitric oxide, DPP4, blood cosinophils, blood neutrophils, sputumcosinophils, IgE, or other biomarkers indicative of the presence orabsence of eosinophilic, neutrophilic, paucigranulocytic, mixedgranulocytic, Th2 or Th1 type inflammation, spirometry and other lungfunction tests, allergies, past history of medications, currentprescribed medication including dose and frequency, means to trackmedication usage, genetic data, weather, allergen levels and particulatematter sensor data. This creates a database with more accurate datadescribing the patients' condition.

Further embodiments may include alert systems and services such astrained healthcare professionals monitoring the data to assist in themanagement of the health of a population either in traditional methodsor proactive intervention.

Embodiments of the invention use materials and manufacturing techniquesto produce test strips in high volume at low-cost for the measurement ofgas in various industries and environments. The test strip may measure asingle gas or multiple gases. Embodiments of the invention may applydifferent sensing chemistries, configurations and layers to the teststrip based on the gas of interest, and the environment in which thetest strip will be placed. The tests strips may be configured to providequalitative and/or quantitative analysis of a gas, or gases. The teststrip may be combined with other devices, or stand alone. Other devicesmay be used control the delivery of the gas of interest to the teststrip, or to process a signal from the test strip. Control may include,but is not limited to, flow, filtration, pre-treatment, etc.

System: One embodiment of the invention is a test strip for use in themedical industry to measure exhaled nitric oxide in human breath. Thetest strip and accompanying devices may be single patient, or multiplepatient uses. The devices, device components and test strip may bedisposable, reusable or any combination. The data gathered from theresult of using the test strip, in this example, exhaled nitric oxidebreath test, may be part of a larger patient monitoring system or maystand alone. FIG. 1 provides an example of a patient monitoring system[101] whereby the patient performs a nitric oxide breath test [102] byinhaling and exhaling through one embodiment of the invention. Theinformation is combined with additional data from the patient, [103] andthat data is stored remotely [104]. The stored data may be combined withinformation from multiple patients for analysis. Measuring multiplegases in the breath stream, ratios of a gas or gases, and/or theduration of exhalation is possible without deviating from the spirit ofthe invention.

In another embodiment the invention is configured to perform a HydrogenBreath Test. The test strip or strips are configured to measure at leastone of the following gases: hydrogen, methane, carbon dioxide. Measuringmultiple gases in the breath stream, ratios of a gas or gases, and/orthe duration of exhalation is possible without deviating from the spiritof the invention.

In another embodiment, the invention is configured to perform a UreaBreath Test. The test strip or strips are configured to measure at leastone of the following gases: carbon dioxide, ammonia. In otherembodiments, the system is configured to measure the ratio of carbonisotopes. In other embodiments, the system is configured to measureratios of carbon isotopes. Measuring multiple gases in the breathstream, ratios of a gas or gases, and/or the duration of exhalation ispossible without deviating from the spirit of the invention.

In another embodiment, the invention is configured to perform a DiabetesBreath Test. The test strip or strips are configured to measure acetonein breath. Measuring multiple gases in the breath stream, ratios of agas or gases, and/or the duration of exhalation is possible withoutdeviating from the spirit of the invention.

In another embodiment, the invention is configured to perform a CancerBreath Test. The test strip or strips are configured to measure volatileorganic compounds in breath. Measuring multiple gases in the breathstream, ratios of a gas or gases, and/or the duration of exhalation ispossible without deviating from the spirit of the invention.

Device Configuration: Embodiments of the invention may be configured innumerous ways without deviating from the spirit of the invention.Configurations may vary to optimize sensitivity and selectivity to thegas of interest, as well as to improve patient experience and ease ofuse. FIG. 2 is an example of one configuration. The patient [201]inhales and exhales through the top of the device [202], and a signal iscaptured by an electronic device [203] in communication with the testingsystem [218]. The testing system [218] may be comprised of an optionalmouthpiece [205], a means of controlling and conditioning the gas flow[206], one or more test strips [208] placed inside the device, and anelectronic device for interpreting the signal from the test strip [204].The electronic device [204] may be in communication with anotherelectronic device(s), such as a phone [203], tablet, or computer, eitherwirelessly, or via a wired connection.

In one embodiment, a test strip [215] is connected to an electronicreading device [216] and placed inside the gas conditioning and flowcontrol unit [219]. The patient [209] inhales through the mouthpiece[220] drawing air in through the bottom of the device [210]. The air maybe conditioned in a chamber [212] to remove the analyte gas or gasesfrom the ambient air. The patient exhales [213] through the mouthpiece.The chamber [214] may be designed to control the flow rate to the teststrip [215] and/or to mechanically induce a set flow rate from thepatients' breath stream. The air may pass over the test strip [215] andout of the device [217], or a portion, or all, of the gas stream may becaptured for immediate, or future analysis. In another embodiment aportion of the gas stream is diverted to the test strip as show in FIG.15, FIG. 16 and FIG. 17.

FIG. 3 provides examples of variations of the assembled device and thetest strip. The device [311] may incorporate a removable and/ordisposable mouthpiece [301]. The unit for controlling and conditioningthe gas stream [312] may be a single piece with a slot for test stripinsertion [310] or multiple pieces [304 and 305] that are separableallowing for insertion of the test strip [303 a] into the gas stream[313]. The unit for controlling and conditioning gas may be a singlechamber or multiple chambers [214] [212]. The electrical device forreading the test strip output [302] may be in wired or wirelesscommunication with a phone [308] or other device. In other embodimentsthe electronics handle the signal processing and display the result[309] or [307]. The test strip may be placed into the gas stream in anyorientation. Horizontal [303 a] and vertical [303 c] test striporientations are shown.

Electronic Test Strip Reader: FIG. 4a and FIG. 4b demonstrate examplesof variations of the Electronic Test Strip Reader, hereafter referred toas “Reader”. Generally speaking, the Reader is designed to provide asignal output from the test strip. The Reader may include means forproviding power, collecting data, signal processing and interpretation,controlling the number of uses, running diagnostics, running ameasurement, communicating with another device (e.g. phone or computeror tablet), etc. In one embodiment, the test strip and Reader areconfigured to measure the resistance change across two or moreelectrodes as the gas of interest interacts with the sensing chemistry.In another embodiment, the test strip and Reader are configured tomeasure the current or voltage across two or more electrodes of the teststrip as the analyte gas or gases interact with the sensing chemistry.The electrodes may be configured as a simple chemically sensitiveresistor (chemresistor), as a field effect transistor, or as Wheatstonebridge, or as a working and counter electrode, or as a working andcounter and reference electrode. Examples of detection methods (e.g. theelectronic and test strip configurations) are chemresistive, fieldeffect transistors, amperometric, potentiometric or voltammetricsignals. The test strip and corresponding electronics may be configuredin a bridge circuit. One of skill in the art would understand that theelectrodes may be made from a variety of conductive materials. In someembodiments the electrodes contain carbon or silver or gold. In someembodiments the electrodes are spaced less than or equal to 2.5millimeters apart.

In some embodiments the resistance or voltage is measured at least oncebefore the sample is applied. In other embodiments the resistance orvoltage is measured at least once during sample application. In stillfurther embodiments the resistance or voltage is measured at least onceafter the sample has been applied. In some embodiments the user of thesystem takes multiple measurements over the course of several hours. Insome embodiments the user of the system takes multiple measurements overthe course of several days, weeks, months or years. In some embodimentsthe total measurement time is less than 1 day, between 30 and 60minutes, between 10 and 30 minutes, 1 and 10 minutes, less than or equalto 1 minute, less than or equal to 30 seconds, less than or equal to 10seconds, less than or equal to 3 seconds.

In one embodiment, a test strip [402 a] is plugged into to a Reader[404]. The Reader [404] is in communication with a mobile phone or othercomputing device [401] via a wired connection [403 b] or by wirelessmeans [403 c]. Examples of wireless communication include, but are notlimited to Bluetooth, WiFi, RFID, Near Field Communication, etc. TheReader [404] may be configured as an adaptor to connect the test stripto a mobile device via the audio output jack, micro-usb or mobile phonemanufacturer's proprietary technology (e.g. Apple).

In another embodiment of the invention [405], the test strip [402 b]communicates directly with a computing device [406]. Communication maybe established by directly docking the test strip into the mobile deviceor by integrating wireless technologies described above directly intothe test strip.

Another embodiment of the electronic systems includes an integratedReader [407] that accepts a test strip [402 c]. The integrated Reader[407] processes the measurement from the test strip [402 c] andinterprets and displays the result of the test [408].

FIG. 4b demonstrates various configurations of the bottom portion [305]of a device [311] described earlier in FIG. 3. In one embodiment [413],the test strip [408 a] is vertically aligned in the gas stream andconnected into the bottom portion [305] of the device [311]. The bottomportion of the device [305] may consist of at least one chamber or mayhave multiple chambers [411] and [412] to allow the flow of gas throughvents [414] and [409]. The gas may be filtered or conditioned during theinhalation phase using filter [410].

In another embodiment, the Reader [415] does not accept the test stripdirectly. The Reader [415] is configured to supply power and measurementcapabilities via electrical contacts [423]. The test strip [408 b] maybe in electrical contact with electrodes [424] and connected to themeasurement device by joining the two electrodes [423] and [424]. Image[424] may also represent holes in the device [416] allowing theelectrodes [423] to connect to the test strip [408 b].

Image [419] illustrates one configuration of the test strip [408 d],reader [420] and bottom portion of the gas control device [425].

The electrical unit may also be integrated into the bottom portion ofthe device as shown in [417] and [421]. In the configuration shown in[417] the unit may have no chambers. The electrical unit [421] may alsohouse additional components such as a temperature sensor [423], a UVsource [426] or a heating element (not shown). The electrical unit mayalso connect to the device wirelessly, for example via induction wherebydata and power may be transferred.

FIG. 17 demonstrates one embodiment of the device incorporating theconcepts of FIG. 15 and FIG. 16 described below. In one embodiment, thedevice [1701] folds. In one embodiment, the unfolded device [1702]contains an electronic reading portion [1703] and a gas conditioningportion [1704] that are connected. In one embodiment, the gasconditioning portion [1704] may accept a filter [1705]. The electronicreader may accept the test strip in various locations. Two examples[1706] and [1707] are show, but this is not intended to be exhaustive ofall the configurations. FIG. 17a demonstrates one embodiment of theconcepts described in FIG. 15, FIG. 16 and/or FIG. 17. A patient [1730]exhales through the device [1708] and the breath stream is diverted[1710] over the sensor [1709].

In one embodiment, the electronic reader show in FIG. 17a , contains adisplay. In one embodiment, the display provides feedback related to theexhalation flow rate. In one embodiment, the display shows the result ofthe test.

The electrical unit [1703] may also be integrated into the device [1702]as a whole shown in FIG. 17. In another embodiment, the signal may befrom an optical measurement of the sensing chemistry.

FIG. 17b demonstrates one embodiment of the invention wherein the readerand gas conditioning system are incorporated into a device [1711]. Thedevice is comprised of a display [1712] connected to a base [1715]. Inthis example the base [1715] is show without a cover. The test strip[1713] is inserted into a chamber [1721], which is located in the device[1711]. The chamber may be designed to create laminar or turbulent flow.The chamber may have an entrance path for a fluid sample. The chambermay also contain an exit path for a fluid sample. In one embodiment, thedevice [1711] either contains or accepts a mouthpiece [1716] for apatient to inhale and/or exhale through the device. In one embodimentthe mouthpiece [1716] contains a bacterial filter.

In one embodiment, the patient inhales through the mouthpiece [1716].The inhaled air stream passes through a channel [1718] before themouthpiece [1716]. The patient then exhales through the mouthpiece anddown a second channel [1719]. In one embodiment the second channel[1719] allows for the exhaled breath to exit the device. In anotherembodiment, the exhaled flow rate is measured. In one embodiment, aportion of the exhaled stream may be diverted through a third channel[1720]. In one embodiment, the channel [1720] is in fluid connectionwith the chamber [1721]. In one embodiment, the channel [1720] iscomprised of a nafion tube. In another embodiment, the channel [1720]contains a filter for removing unwanted analytes. In another embodiment,the channel [1720] is designed to perform multiple functions. In anotherembodiment, the channel [1720] is designed to dry the breath stream. Inone embodiment, the channel [1718] contains a filter to remove unwantedanalytes from the ambient air. In another embodiment, the chamber [1721]and/or fluid channels [1718], [1719], [1720] and/or mouthpiece [1716]may contain a valves, flow restrictors, or sensors. In anotherembodiment the device [1711] contains a vent.

In one embodiment, the display folds on top of the base [1714].

In another embodiment, the device [1711] contains additional sensors.Examples include but are not limited to temperature, humidity, flow,gases (e.g. carbon monoxide).

FIG. 17c demonstrates an embodiment of the invention wherein the output[1727] of the device [1722] is selected from a plurality of endpoints.In one embodiment, the measurement of resistance or voltage correspondsto at least one of a plurality of analyte concentration ranges. In oneembodiment, the outputs are quantitative or semi quantitative. Inanother embodiment, the outputs are qualitative. In yet anotherembodiment, the endpoints may be determined from the age of the patient.The endpoint for an age less than 12 correlates to three ranges ofanalyte concentrations (i) less than 20 parts per billion, (ii) between20 and 35 parts per billion, (iii) greater than 35 parts per billion ofthe analyte. The endpoint for an age greater than 12 correlates to threeranges of analyte concentrations (i) less than 25 parts per billion,(ii) between 25 and 50 parts per billion, (iii) greater than 50 partsper billion of the analyte. In another embodiment, the device [1722] maydetermine the type of output based on the input received from one or aplurality of sources. In some embodiments, the output is above or belowa pre-determined analyte concentration. In some embodiments, the pre-setanalyte concentration is selected from a range of concentrations between1 and 50 parts per billion. When the analyte is nitric oxide the pre-setanalyte concentration may preferably be 20 parts per billion, 25 partsper billion, 30 parts per billion, 35 parts per billion, 40 parts perbillion, 50 parts per billion. When the analyte is methane thepreferable pre-set analyte concentration is 15 parts per million or 20part per million. When the analyte is hydrogen the preferable pre-setanalyte concentration is 15 parts per million or 20 part per million.

In one embodiment, the test strip [1725] may contain electrodes in aspecific configuration or of a specific resistance indicating to thedevice the type of output to display [1727]. In another embodiment, abar code [1724] is used to determine the type of output to display. Thebar code may be located in any number of places without deviating fromthe spirit of the invention. Examples include but are not limited to thetest strip [1725] or packaging [1723]. In another embodiment, a chip[1726] is inserted into the device [1722] to provide informationregarding the at least one of a plurality of outputs. In anotherembodiment, the type of output is manually entered into the device.

In another embodiment, the bar code or chip may also enable the deviceto utilize a specific calibration table. In another embodiment, the barcode or chip may contain information pertaining to a calibration table.

In another embodiment, information regarding the plurality of outputs orinformation regarding calibration is received from a paired mobilecomputing device.

Gas Preparation, Conditioning and Flow Control: Various embodiments andconfigurations are possible without deviating from the spirit of theinvention. Configurations are dictated by the characteristics of thetest strip, sensing chemistry, analyte of interest and environment inwhich the unit will be placed. Generally speaking, the gas preparation,conditioning, and flow control device may come in a variety of shapes,sizes, and contain any combination of chambers, structures, valves,filters or vents designed to deliver the analyte to the test strip. Thedevice hereafter is referred to as the Gas Control Device. Anon-limiting list of examples of Gas Control Devices includes: Bowtievalve, Mechanical iris, Ball and taper, Leuver vent, Filters, Membranes,Sieve (e.g. molecular sieve), Activated Carbons, Swinging gate, Seesawvalve, Poppet valve, Diaphragm valve, Tapered chamber, Fixed orificesize, Deformable orifice, Piston valve, Elastomericvessel/tube/structure, Iris and paddle wheel combination (Two discs withslots that line up. Spring open. Higher pressure/flow rate rotates thedisc(s) to open. Lower pressure/flow rates the disc(s) spring backclosed), Flapper valve, Spring valves, Mushroom valve, Check valve,Balloon with holes, Balloon in a balloon (Optionally one balloon hasholes), Pressure regulator, Mass Flow Controller, Bennet Valve, Port(s)Valve, Choked Flow, Sonic choke, One way valve, Single-stage pressureregulator, Two-stage pressure regulator, Expandable reservoir,Liquid-Vapor pressure, Back-Pressure regulator/relief valve, Elastomericflow regulator, and Variable orifice valve. Springs may also be used incombination with the items listed above, Further, any combination of theabove items can be used to achieve the desired pressure and/or flowrate. Further, one of skill in the art would recognize that multiplevariations of the valves and valve concepts listed above are possible.

FIG. 5a and FIG. 5b demonstrate embodiments of various mechanisms tocontrol the flow of gas to the test strip and methods of filtering thegas stream. An optional mouthpiece [501] may contain a bacterial filter[502] to enable device sharing among several patients, or to provide afiltered environment to the device downstream. The optional mouthpiece[501] is positioned proximally to the Gas Control Device [504]. In oneembodiment, the Gas Control Device [504] is configured to measureexhaled nitric oxide in human breath. The Gas Control device [504] mayconsist of a series of mechanisms, such as chambers, valves and/orfilters. Filters may include items such as gas diffusion barriers,activated micro and nanostructures and selectively permeable membranes.Alternatively, a filter may be a high surface area material, such as acopper microbead-polytetrafluorethylene composite or reactive metalmesh. Other embodiments may include filters or membranes that have beenfurther impregnated, coated or treated to serve dual purposes (e.g.nafion coated PTFE). The patent positions their mouth proximal to themouthpiece and inhales through the mouthpiece [501]. Air is drawn inthrough a vent [515] into a chamber [511]. The chamber may contain oneor more filters [516] designed to remove ambient gases from the air. Thechamber [511] is in fluid connection with [505] so that the air can bedrawn through a one-way valve [503] and into the patients' lungs. Thepatient immediately exhales. The exhaled breath stream [506] passes intothe area [508] and the flow rate is mechanically controlled by amechanism, such as a valve, or series of valves [507], which only allowsgas to pass at a pre-specified flow rate above a pre-specified pressure.In a preferred embodiment, the flow rate is between 10 ml/sec and 100ml/sec, the pressure is between 5-20 cm H₂O. The gas interacts with thesensor [513] and out a one-way valve [509]. The one-way valve [509] maybe designed to close as the patients exhalation pressure drops near theend of the exhalation. This would cause the last several seconds of thebreath stream to be trapped in the chamber [508] and be measured by thetest strip [513] and Reader (not shown). Trapping the air allows fordiffusion of the gas through at least one layer on the sensor and/or toallow for time for a chemical reaction to occur.

Another embedment [504 a] is a similar design to the gas control unit[504]. The main difference is that the one way valve [509 a] ispositioned in the bottom portion of the gas conditioning unit [513 a].This allows for direct flow of the gas over the test strip and passesout through the bottom of the device. When this valve closes, exhaledbreath is trapped in the chamber [508 a].

Yet another embodiment does not involve trapping the gas and is shown inexample [504 b]. The embodiment is essentially the same as 504 and 504 abut it does not contain a valve [509] or [509 a] for trapping air in thechamber [508] and [508 a].

In one embodiment the flow is measured by measuring pressure across anorifice. In another embodiment, flow rate is calculated by measuringpressure before an orifice.

In another embodiment, the exhaled breath stream is diverted as show inFIG. 15 and FIG. 16.

Other embodiments of the gas conditioning device are show in FIG. 5b[517], [518], [519] and [520]. Examples [516], [517] and [518] functionsimilarly to [504]. The primary difference in example [517] is that thevalve configuration [507] is replaced with at least one filter [521].The filter(s) may control the gas flow in addition to conditioning thegas sample. Examples of conditioning relate to removing water vapor, andfunctioning as a diffusion barrier or semipermeable membrane to removeinterfering gases.

In another embodiment, the gas control unit is chemically treated (e.g.with Nafion to remove humidity from the gas stream) to provideconditioning effects.

Example [518] differs from [504] in that the positioning of the filterand vent [523] is integrated into the top portion [524] of the gasconditioning device instead of the bottom portion of the gasconditioning device.

Example [519] differs from [504] in that at least one filter [526] isplaced proximally to the test strip in the exhaled gas stream.

Example [520] shows an embodiment of the gas control unit with a singlechamber [527], and a mechanism to control the flow rate.

FIG. 5c demonstrates two additional embodiments [529] and [531].

Example [529] shows an embodiment of the gas control unit with a singlechamber [530] without a mechanism to control the flow rate.

Example [531] shows an embodiment of the gas control unit with twochambers [532] and [533]. One chamber [533] allows for inhalationthrough the device. The other chamber [532] allows for exhalationthrough the device. In one embodiment, the test strip is placed in thefluid path of the exhaled air.

FIG. 6a demonstrates an example of the test incorporated into a balloonor vessel. In one embodiment [601] a gas conditioning device [604] asdescribed in earlier is attached to a balloon [606]. The balloon is madeof materials that will not interact with the gas of interest and willminimize gas diffusion through the sidewall. These materials mayinclude, but are not limited to, plastics, such as polyester,polypropylene, polyethylene terephthalate, polyimide, etc., or metalfoils, such as copper, aluminum etc., or graphitic materials, such asgraphene, or graphene oxide thin films. In a preferred embodiment, theballoon is made of Teldar or Mylar. The balloon may be configured as arolled tube [617], or as an empty bag [606] and may have either an openor closed end as show in, [601], [602, 609], [603, 614].

Embodiments may include a test strip [605] inserted into the gasconditioning device [604] and connected to a measuring device (notshown). Another embodiment of the device [602] includes a gasconditioning unit [608] connected to a balloon. The test strip [616] canbe deposited directly on the balloon or pre-assembled and attached tothe balloon. The distal end of the balloon has a mechanism [609] thatallows for the flow of exhaled breath [615] to pass through the device.When the pressure changes from the last portion of the breath maneuver,the mechanism closes trapping the gas in the balloon with the test stripfor reading. Another embodiment [603] contains a vessel, tube, orballoon [612] inside another vessel, tube, or balloon [616]. Theinternal vessel [612] is treated to selectively allow the gas ofinterest [615 a], [615 b] to pass through into the outer vessel [616]where it may interact with a sensor [610 a]. A portion of the gas stream[615 a] may also exit the device.

FIG. 6b is an example of one embodiment where the balloon [622] isattached to a gas control device [621]. The patient fills the balloon[622] with expired breath. A test strip [619] is inserted into theReader [618] via a slot [620]. The balloon containing expired breath isconnected to a Reader via an opening [612] for measurement. The samplemay be drawn into the Reader [618] via a pump or by a spring/wire in theballoon [622] designed to recoil the balloon to a rolled position asshown in [617].

In some embodiments the system may further comprise a meter configuredto deliver at least a portion of the fluid sample to at least thesensing chemistry. The meter may comprise, stainless steel, aluminum,siliconized materials, glass, Teflon, Teflon-coated material, plastic orK-resin. The meter accepts a fluid sample, which may be exhaled breath,from a human. The meter may positively restrict the pressure of thefluid sample. Preferably when the meter positively restricts thepressure of the fluid sample the pressure is between 5 cm/H20(centimeters of water column) and 20 cm/H20. The meter may provide anoutput correlating to an analyte concentration.

FIG. 7 demonstrates examples of various orientations of the test stripwithin the device. The test strip may be oriented horizontally [701],[703], [704] or vertically [702], or at some other angle. The sensingchemistry may be oriented towards the gas stream [701] and [703] or awayfrom the gas stream [704].

FIG. 8 is an example of the devices configured to peel or pierce aprotective layer from the test strip. In one embodiment [801] the teststrip [803] has a protective cover [804] that is pierced by a structure[805] when the device is assembled for use. In another embodiment [802],the protective cover [807] on the test strip [804] is peeled by astructure [806] when inserted into the device.

FIG. 15 is an example of diverting the gas stream from an exhaled breathto the sensor. In one embodiment, the patient [1501] exhales through adevice referenced herein at a flow rate. A portion of the exhalation[1502] is diverted [1503] to a sensor [1504]. In one embodiment the flowrate is 3000 standard cubic centimeters per minute (SCCM)±10%. Inanother embodiment the flow rate is 3000 SCCM±5%. In one embodiment, theflow rate of the diverted gas stream is less than the exhalation flowrate. In another embodiment, the flow rate of the diverted gas stream isless than 3000 SCCM. In another embodiment, the flow rate of thediverted gas stream is less than 500 SCCM. In another embodiment theflow rate of the diverted gas stream is less than 350 SCCM. In anotherembodiment the flow rate of the diverted gas stream is between 1 SCCMand 3000 SCCM. In another embodiment, the diverted gas stream is passedthrough a Nafion tube.

FIG. 16 is similar to FIG. 15 and also includes an inhalation maneuver[1605] by the patient [1601] to remove certain ambient gases from theair. A portion of the exhalation [1602] is diverted [1603] to a sensor[1604]. In one embodiment, the ambient gas is NO. In another embodiment,the ambient gas is NO₂. In another embodiment, both NO and NO₂ areremoved.

FIG. 17 demonstrates one embodiment of the device incorporating theconcepts of FIG. 15 and FIG. 16. In one embodiment, the device [1701]folds. In one embodiment, the unfolded device [1702] contains anelectronic reading portion [1703] and a gas conditioning portion [1704]that are connected. In one embodiment, the gas conditioning portion[1704] may accept a filter [1705]. The electronic reader may accept thetest strip in various locations. Two examples [1706] and [1707] areshow, but this is not intended to be exhaustive of all theconfigurations. FIG. 17a demonstrates one embodiment of the conceptsdescribed in FIG. 15, FIG. 16 and/or FIG. 17. A patient [1730] exhalesthrough the device [1708] and the breath stream is diverted [1710] overthe sensor [1709].

In one embodiment, the electronic reader show in FIG. 17a , contains adisplay. In one embodiment, the display provides feedback related to theexhalation flow rate. In one embodiment, the display shows the result ofthe test. Feedback may also be audio feedback or based on resistance.

Other embodiments allow for the elimination or separation of “deadspace” in the airway to ensure measurements are taken from the alveolarspace. Dead space is the volume of air which is inhaled that does nottake part in the gas exchange of oxygen and carbon dioxide, eitherbecause it remains in the proximal airways, or reaches alveoli that arenot perfused or poorly perfused. Dead space separation or eliminationmay be done mechanically or with software (e.g. calculate the durationof a exhalation and ignore the first portion of the breath stream)

Test Strip—General: At its most basic level, the test strip is comprisedof a substrate/base and sensing chemistry. Embodiments of the test stripinclude a substrate, a means of establishing an electrical connection(i.e. electrode), at least one sensing chemistry and at least oneadditional layer. The configuration and design may be modified based onthe gas of interest and environment in which the test strip will beplaced. The sensing chemistry is selected based on the gas of interest,and the electrodes are configured to measure the chemical reaction thatoccurs. The layer, or layers, may severe multiple purposes including,but not limited to, support for the sensing materials and chemistry,sensing the analyte, masking for chemistry deposition, adhesion betweenlayers, protection from interfering substances, enhancing theselectivity and/or sensitivity of the test strip and spacing. Detailsregarding the electrode, the chemistry, and the layers are describedbelow.

In some embodiments the test strip is single use. In some embodimentsthe test strip is multi use. In some embodiments the test strip islimited use. In still other embodiments the test strip can be used forless than or equal to three uses.

Test Strip Sensing Chemistry: Many sensing chemistries are possiblewithout deviating from the spirit of the invention. In one embodiment,the sensing chemistry is comprised of nanostructures functionalized tobind to an analyte causing an electrical resistance change across thenanostructures. In other embodiments the analyte causes a redox reactionat the nanostructural level which is measured. In another embodiment,the analyte causes a change in the surface electrons of the sensingchemistry, resulting in changes in the optical characteristics, whichare measured. Nanostructures may include, but are not limited to, carbonnanotubes (single walled, multiwalled, or few-walled), nanowires,graphene, graphene oxides etc. The nanostructures can be assembled toform macroscopic features, such as papers, foams, films, etc. or may beembedded in or deposited on macrostructures. Examples offunctionalization materials include:

Heterocyclic macrocycles

-   -   a. Examples include but are not limited to: crown ethers,        phthalocyanines, porphyrins etc.

Metal oxides

-   -   a. Examples include but are not limited to: AgO, CeO₂, Co₂O₃,        CrO₂, PdO, RuO₂, TiO₂

Transition metals

-   -   a. Examples include but are not limited to: Ag, Cu, Co, Cr, Fe,        Ni, Pt, Ru, Rh, Ti

Carboxyl groups

-   -   a. Examples include but are not limited to: Carboxylic acids

Functional Organic Dyes

-   -   a. Examples include but are not limited to: Azo dyes, Cyanines,        Fluorones, indigo dyes, photochromic dyes, Phthalocyanines        Xanthens, etc.

The functionalized nanostructure, hereafter referred to as sensingchemistry, is disposed over a substrate to form the basic components ofa test strip. Electrodes are in communication with the sensing chemistryas described below.

In another embodiment, the sensing chemistry is a non-functionalized(i.e. un-sensitized) nanostructure. This embodiment may be used inconjunction with a functionalized nanostructure or it may stand-alone.

Secondary additives may be used to affect the drying characteristics andprocess ability of the sensing chemistry for deposition onto asubstrate. Non limiting examples of deposition methods are listed inFIG. 14. Additives may be used to change the viscosity, surface tension,wettability, adhesion, drying time, gelation, film uniformity, etc.These additives include, but are not limited to, secondary solvents,thickeners, salts, and/or surfactants. These additives may serve one ormultiple purposes. Examples may include, but are not limited to, thosein FIG. 10 and:

Thickeners—polymeric and non-polymeric

-   -   a. Glycerol    -   b. Polypropylene glycol

Surfactants—ionic and non-ionic

-   -   a. Sodium dodecyl sulfate    -   b. Triton X-100

In some embodiments, the volume of sensing chemistry disposed on thesubstrate maybe less than or equal to 1 milliliter of material.

Test Strip—Substrate, Electrode and Sensing Chemistry Configuration:Various configurations or combinations of the substrate, electrode, andchemistry deposition are possible without deviating from the spirit ofthe invention. Configurations are dictated by the characteristics of thesensing chemistry, analyte of interest, and the environment in which theunit will be placed. Sensing chemistries may also be coated to preventanalyte interaction, so as to provide a reference, as in a chemresistivebridge circuit. Multiple sensing chemistries may be used, or the samechemistry may be deposited more than once, to serve as a reference, formultiplexed analysis, or for signal averaging. FIG. 9a and FIG. 9b showsexamples [901 through 912 and 922 through 926] of various configurationsof substrate, electrode, and sensing chemistries on one layer of thetest strip.

In one embodiment [901] a substrate [913] contains electrodes [914] anda sensing chemistry [915] deposited across the electrodes [914] on oneside. The reverse side of the substrate [916] also contains electrodesand a sensing chemistry. The reverse side of the substrate [916] may besymmetric or asymmetric. Asymmetry may include different sensingchemistries, chemistry or electrode configurations, etc. The secondsensing chemistry [917] may the same or different from the first sensingchemistry [915]. This may be used to adjust sensitivity and selectivityto the analyte of interest. In another embodiment [908], two test stripsare manufactured separately [932] [931] and then assembled onto aseparate substrate [918] to form a finished test strip. This may be doneto increase the case of manufacturability if the sensing chemistries aredifferent. In another embodiment in which the sensing chemistries areside by side [909], one of the two sensing chemistries is covered [921].In another embodiment [911] the substrate [922] allows for the passingof gas [921 a] through it to the sensing chemistry. This allows for thetest strip to be placed facing away from the gas stream as describedearlier in FIG. 7 ([705]). Examples of additional configurations [922]and [923] are shown with two chemistries offset on the test stripsharing one electrode. In one example [923] one of the two chemistriesis covered. In another embodiment [924], multiple sensing chemistriesare shown. In this example, the chemistries may share at least oneelectrode. In another embodiment [925], at least one of the chemistriesis covered. In another embodiment [926], shows a chemistry bridgingthree electrodes. In this embodiment, the three electrodes may representa working, reference and counter electrode.

FIG. 9c shows embodiments of more complex configurations. In certainembodiments, [927], [928], and [929], an integrated heater [931], [933],[934] is incorporated into the test strip either on the same layer asthe sensing chemistry [932 a], [932 b], [932 c] (as show in [928]) or ona different layer (as shown in [927]). In other embodiments [929] thetest strip has additional sensor elements [935] and integratedelectronics [936] on at least one layer. Examples of additional sensorelements [935] may include, but are not limited to, temperature, and/orhumidity sensors. Examples of integrated electronics [936] may include,but are not limited to, resistors, fuses, capacitors, switches, etc. Thetest strip may also include a means for managing or controlling thenumber of uses (not shown). Examples include RFID, barcodes, circuit orfuse burn out, memory on the test strip, serial number, switch, etc.

In other embodiments, the heater, additional sensor elements, andintegrated electronics described herein are incorporated into thereader.

In other embodiments, the heater, additional sensor elements, andintegrated electronics described herein are incorporated into the readerand/or the chamber in which the test strip is placed.

Other examples (not shown) may include an electrode configurationsuitable to measure an electrochemical reaction (i.e. working electrode,counter electrode, reference electrode).

In one embodiment, the test strip may be comprised of a substrate, atleast one electrode, at least one sensing chemistry, and, optionally, atleast one layer to protect the sensing chemistry from interferingsubstances. The sensing area may consist of at least two nanonetworks inelectrical communication with one or more electrical contacts. Onenetwork will act as the active sensing chemistry and will be sensitiveto a particular set of analytes (e.g. nitric oxide). Additional networkswill act either as a reference, as sensors for different analytes, orfor the same analyte for signal averaging. The reference may besensitive to a different set of analytes such that the differentialsignal between the active sensing chemistry, and the reference resultsin signal sensitivity towards a single analyte, a small set of analytes,or a subset of analytes with which the test strip is sensitive. In thecase of multiplexed analysis, there may be more than one reference.

In another embodiment, the test strip may be comprised of a substrate,at least one electrode, at least one sensing chemistry, and optionallyat least one layer to protect the sensing chemistry from interferingsubstances. The sensing area may consist of at least two nanonetworksdeposited between two or more electrodes. One network will act as theactive sensing chemistry and will be sensitive to a particular set ofanalytes (e.g. nitric oxide, carbon dioxide, hydrogen, or methane). Thesecond network will act as a reference. The reference may consist of thesame sensing chemistry as the active nanonetwork and may be covered oruncovered. The test strip and chemistries may be configured as aresistive circuit or bridge circuit.

In some embodiments the active chemistry and sensing chemistry arepre-mixed before deposition on the substrate. In some embodiments theactive and sensing chemistry are deposited in less than or equal to foursteps.

In another embodiment, the test strip and reader may be configured tomeasure a gas concentration in breath or flatulence that is the resultof the interaction between a substance (e.g. fructose, lactose, sucrose,isotopes, etc.) and a human or animal body. Substances may be inserted,ingested, digested, inhaled, injected or transmitted through the dermis(i.e. transdermal patch). Examples include but are not limited toHydrogen Breath Test (which may also include methane and/or carbonmonoxide and/or carbon dioxide measurement) or Urea Breath Test. Otherexamples may include substances that interact with cancers, tumors,blood, viruses, bacteria, prions, parasites etc. to produce a gas thatis measured. In these embodiments a gas delivery device is optional.

Test Strip—Layers: FIG. 11 shows examples of a test strip with multiplelayers. Layers may be incorporated into the test strip for a variety ofreasons depending on the sensing chemistry, electrode configuration,interfering substances and manufacturing process. Examples include butare not limited to: masking for chemistry deposition, support forchemistry deposition, protection from interfering substances, enhancingthe selectivity and/or sensitivity of the test strip, acting as thesensing chemistry, spacing, formation of gas chamber(s), test striprigidity or structural configuration. Layers may be comprised of porousand non-porous polymers, composite materials, fibrous materials such aspaper or fiber glass, woven and non-woven textiles, membranes, polymers,adhesives, films, gels, etc. The layers may be modified, for example, bychemically treating or coating and/or mechanically altering. The layersmay serve one, or more than one, purpose. For example, a layer may serveas a structural component (e.g. improve rigidity or as a spacer), and aselective gas permeable membrane. Layers may be used in conjunction witheach other to provide selective permeation of the gas of interest whileprotecting the test strip from interfering substances. In someembodiments there is a dielectric layer disposed above the electrodes.

As shown in the dual chamber example [1121], spacing layers [1125] mayalso be used to create a single chamber or multiple chambers [1126]. Thespacing layer [1125] is disposed above the substrate with the electrodeand sensing chemistry [1127]. The chambers may be uniformly covered ordifferentially covered [1135]. In one embodiment, the differentiallycoated chambers allow for different gases to diffuse into the differentchambers in order to be sensed by the sensing chemistry. In anotherembodiment [1122] a gas selective layer [1130] is disposed above thesubstrate with the electrode and sensing chemistry [1127]. The spacinglayer [1125] containing a small single chamber [1129] is disposed abovethe gas selective layer [1130]. A humidity barrier is disposed above thespacing layer and covering the small chamber [1128]. In anotherembodiment [1123] two spacing layers [1125] are used. The two spacinglayers may be used to create a larger chamber for the gas to accumulateat the sensor surface or to separate multiple diffusion layers. Thespacing layers may also serve as structural support for the test stripand its layers. A Nafion layer [1133] is disposed above the substratewith the electrode and sensing chemistry [1127]. A spacing layer [1125]is disposed above the Nafion layer [1133]. A selective diffusion layer[1132] is disposed above the first spacing layer [1125]. A secondspacing layer [1125] is disposed above the selective diffusions layer[1132]. A foil barrier [1131] is disposed above the second spacing layer[1125]. In another embodiment [1124] a different combination of layersis used. A selectively permeable layer [1133] is disposed above thesubstrate with the electrode and sensing chemistry [1127]. Two selectivediffusion layers [1132] and a plug [1134] are disposed above the spacinglayer [1125]. In one embodiment, the plug [1134] functions as a sealingmechanism when a test strip is inserted into a chamber.

Layers may be designed to be reactive to certain gases.

The layers may be applied by various coating methods including but notlimited to those illustrated in FIG. 14.

Examples of interferences may include but are not limited to: gases,condensed liquids, dissolved solids, particulate matter, humidity,temperature variations, etc. In the example of measuring nitric oxide inexhaled breath, examples of interferences may include:

Interfering Substances for Measuring Nitric Oxide in Exhaled Breath

CO₂ C₂H₃N C₂H₄O C₂H₆O C₃H₆O C₅H₈ CO H₂ H₂O H₂O₂ H₂S NH₃ NO₂ O₂ pH

FIG. 11a demonstrates a preferred embodiment. In this example [1100],the test strip includes a base substrate [1101] with electrodes [1106]and a sensing chemistry [1108] and reference chemistry [1107], anoptional dielectric layer [1102], a layer to cover the referencechemistry [1103] and expose the sensing chemistry [1110], a membranelayer [1104], and a protective layer [1105]. The protective layer [1105]employs a means [1111] to allow gas to flow to the membrane layer[1104]. In one embodiment, the membrane layer [1104] contains silicone.

FIG. 12 demonstrates examples of assembled test strips. [1201] depicts afully assembled test strip. Embodiment [1202] depicts test strip with afoil barrier for puncture with a companion device. Embodiment [1203]depicts a test strip with a foil barrier that has a manual removal tab.Embodiment [1204] depicts a test strip with electrodes in the measuringunit rather than on the test strip itself. This this later embodiment,electrodes disposed in a companion device contacts the sensingchemistries on the test strip when the device and test strip are mated.

FIGS. 13, 13 a, 13 b and 13 c show various layouts of the test stripsfor mass production. A continuous substrate from a roll [1301] issupplied for chemistry deposition. The substrate may already includeelectrodes [1304]. The chemistry [1302] is deposited on the continuoussubstrate using any number of methods and coating techniques listed inFIG. 14. This is not intended to be an exhaustive list. Individual teststrips [1303] are cut using methods known in the art (e.g. die cut). Twochemistries can also be deposited [1302] on a continuous substrate froma roll [1301]. Layers [1305] can also be deposited on the continuoussubstrate from a roll [1301]. FIG. 13b depicts an expanded example of asection of the continuous roll. In this example, the section containselectrodes [1304], a chemistry [1302] disposed above the electrodes[1304] and two layers [1305] and [1306] disposed above the chemistry.FIG. 13c depicts deposition of electrodes [1304] and chemistry [1302] inthree rows on a sheet. Any number of rows are possible without deviatingfrom the spirit of the invention. A sheet containing electrodes is fedinto a machine designed to deposit the chemistry. The sheets with thechemistry are then dried by any number of methods. Examples include butare not limited to air drying, convection, heat, infra-red, ultravioletetc. One of skill in the art would appreciate that the additional layerscontain pressure or heat sensitive materials those layers may also beapplied. The sheets may be cut into smaller strips [1303] by any numberof methods known in the art (e.g. die cut).

In some embodiments, the layer that covers the sensing chemistry issubstantially permeable to the analyte of interest. In some embodimentsone of the layers is a blocking layer that covers the reference sensingchemistry and has a window which exposes the active sensing chemistry.In some embodiments the blocking layer may include an adhesive. One ofskill in the art would understand that any of a number of adhesiveswould be adequate, including but not limited to a heat sensitiveadhesive or a pressure sensitive adhesive.

In some embodiments one layer may be a membrane layer that isselectively permeable to at least one analyte. One of skill in the artwould understand that a membrane layer could comprise a number ofdifferent materials, including but not limited to porous polymers,non-porous polymers, composite materials, fibrous materials, woventextiles, non-woven textiles, polymers, adhesives, films, gels, PTFE,and silicone. In some embodiments a silicone transfer layer may be usedto attach the membrane layer to at least one other layer.

The examples incorporated herein primarily relate to gas detectionhowever, the concepts, chemistries, and sensor designs described mayalso apply to detecting other fluids, analytes etc. without deviatingfrom the spirit of the invention. The concepts, chemistries, and sensordesigns described in this invention may also apply to detecting othergases, fluids, analytes etc. without deviating from the spirit of theinvention. This following list provides examples of such applications.The list is not intended to be exhaustive. Industries (non-exhaustivelist): Industrial, Automotive, Environmental, Military, Agricultural,Veterinary, and Medical. Within the Medical Industry specific examples(non-exhaustive list) include: I) Health diagnostics related to thefollowing areas (non-exhaustive list), Clinical chemistry &immunoassays, Breath analysis, Hematology & hemostasis, Urinanalysis,Molecular diagnostics, Tissue diagnostics, Point-of-care diagnostics,Exhaled Breath and/or Condensate, Virology, Analysis of Proteins and/orAntibodies, DNA/RNA, Oncology, Cardiology & metabolism, Infectiousdiseases, inflammatory & autoimmune, Women's health, Critical care, andToxicology; 2) Techniques (non-exhaustive list) including, Polymerasechain reaction (PCR & qPCR), Nucleic Acid Amplification, ELISA, andFluorescence; and 3) Specific Diseases (non-exhaustive list) including,STDs, Breath tests, Digestive Disorders, Urinary LTE4, MRSA, Influenza,Viral detection, and Bacterial detection.

The above techniques, devices, and systems have been described withreference to detecting an analyte in exhaled breath of a patient.However, the techniques devices, and systems are also useful in anyapplication in which it is desirable to detect the presence and/oramount of particular compounds in a gaseous stream, such as theindustrial, automotive, environmental, military, fire and safety,agricultural, and veterinary fields.

Examples of industrial applications include but are not limited toindustries such as oil and gas, manufacturing process, power generation,chemicals, basic materials, mining, commercial building etc. Oneembodiment of the device is used to detect dangerous gases in coal mineand is worn by miners. In another embodiment, the test strip isconfigured to measure gases for quality control purposes inmanufacturing processes that require high purity gases.

Examples of automotive applications include but are not limited tomonitoring air quality in the cabin of the automobile and/or monitoringthe exhaust stream from the engine.

Examples of environmental applications include home safety, airpollution and air quality. In one embodiment, the test strip and readeris placed in multiple locations in an urban area, and the data istransmitted to a central location to monitor air quality.

Examples in the agricultural industry include but are not limited toagricultural production and the food packaging and processing industry.In one embodiment, the test strip and Reader is packaged with food tomonitor spoilage. In another embodiment, the test strip is part of aRFID tag which is packaged with the food to monitor spoilage and readremotely. In another embodiment, the test strip and Reader is configuredto measure methane or other gas concentrations in waste of livestock.

In one embodiment in the military and fire and safety industry, the teststrip is combined with a robot/drone or other means, such as a ball thatcan be thrown. The test strip is then sent into an area without the needfor a human presence to detect gases of interest.

Some aspects of the techniques and systems disclosed herein may beimplemented as a computer program product for use with a computer systemor computerized electronic device. Such implementations may include aseries of computer instructions, or logic, fixed either on a tangiblemedium, such as a computer readable medium (e.g., a diskette, CD-ROM,ROM, flash memory or other memory or fixed disk) or transmittable to acomputer system or a device, via a modem or other interface device, suchas a communications adapter connected to a network over a medium.

The medium may be either a tangible medium (e.g., optical or analogcommunications lines) or a medium implemented with wireless techniques(e.g., Wi-Fi, cellular, microwave, infrared or other transmissiontechniques). The series of computer instructions embodies at least partof the functionality described herein with respect to the system. Thoseskilled in the art should appreciate that such computer instructions canbe written in a number of programming languages for use with manycomputer architectures or operating systems.

Furthermore, such instructions may be stored in any tangible memorydevice, such as semiconductor, magnetic, optical or other memorydevices, and may be transmitted using any communications technology,such as optical, infrared, microwave, or other transmissiontechnologies.

It is expected that such a computer program product may be distributedas a removable medium with accompanying printed or electronicdocumentation (e.g., shrink wrapped software), preloaded with a computersystem (e.g., on system ROM or fixed disk), or distributed from a serveror electronic bulletin board over the network (e.g., the Internet orWorld Wide Web). Of course, some embodiments of the invention may beimplemented as a combination of both software (e.g., a computer programproduct) and hardware. Still other embodiments of the invention areimplemented as entirely hardware, or entirely software (e.g., a computerprogram product).

Moreover, the techniques and systems disclosed herein can be used with avariety of mobile devices. For example, mobile telephones, smart phones,personal digital assistants, and/or mobile computing devices capable ofreceiving the signals discussed herein can be used in implementations ofthe invention.

Embodiments of the invention facilitate gathering biological, medical,therapeutic, environmental and symptom data through a combination ofmobile and web based software applications. The gathering of geneticdata is also within the scope of the invention. The information isgathered by a combination of manual and automatic input from a varietyof interfaces and platforms. Information gathered directly from devicesis also within the scope of the invention. Data from one or a multitudeof patients is stored remotely in an electronically readable catalog,such as a database. The system generates relevant information to allowproviders, payers, patients and industry to monitor, manage, and treatpatients with chronic respiratory diseases.

Under one embodiment, physicians are able to use the invention tomonitor the effectiveness of their prescribed therapy and search for themost effective therapies based on individual patient characteristics.The system provides this information by tracking trends in gathered data(i.e. symptoms, biomarkers etc.) and correlating that information toprescribed therapies. The system may compare the effectiveness oftherapies across the collection of patients or a single patient. Thesystem would allow a physician to enter the characteristics of anindividual patient and implementations of the invention would find likepatients and display therapies that were both successful andunsuccessful. This allows the physician to input characteristics about agiven patient and access successful treatment protocols from thepopulation in the collection to reduce the need for trial and error.

Physicians may also use the invention to identify root causes ofpatients' symptoms. In this embodiment, the system may compare trends insymptom and biological data, correlate it to the prescribed therapy,check against environmental data and/or prescription usage.

Other embodiments use the gathered information to compare drugeffectiveness, monitor adherence to therapy, create risk reports (i.e.for underwriting purposes) or establish payment based on outcomes.

Other embodiments use the gathered information to determine the optimaldose of a drug or drugs based on patient response to treatment asdetermined by biomarker values or a combination of information gatheredby the invention. Examples of biomarkers include but is not limited toscrum periostin, exhaled nitric oxide, DPP4, blood eosinophils, bloodneutrophils, sputum eosinophils, IgE, or other biomarkers indicative ofthe presence or absence of eosinophilic, neutrophilic,paucigranulocytic, mixed granulocytic, Th2 or Th1 type inflammation.

Other embodiments use a biomarker or a combination of biomarkers topredict drug response. Biomarker measurements may be taken at a singlepoint in time or across multiple points. Examples of biomarkers havebeen previously described although it is not intended to be anexhaustive list. Examples of drug response may be defined as improvementin lung function, reduction in exacerbations, reduction in the need forsteroids or rescue medications. Drugs may include those therapiesdesigned to treat chronic respiratory disease.

Other embodiments use the gathered information to determine patientcompliance or adherence to therapy. Compliance may be determined bytaking one or multiple measurements of one or several biomarkers overtime and comparing those measurements to the patient's baseline or knownbiomarker thresholds. Measurements below baseline indicate compliance totherapy. Measurements above the baseline may indicated non-compliance totherapy. Examples of biomarkers have been previously described. This isnot intended to be an exhaustive list.

Other embodiments of the invention use the gathered information todiagnose or identify steroid refractory and/or steroid insensitiveasthma. In one embodiment, steroid refractory or insensitive asthma maybe determined by a patient continuing to show symptoms of asthma despitea high dose of steroid and confirmation of compliance by a biomarker orgroup of biomarkers. This embodiment may also include documenting theuse of a biomarker or group of biomarkers to predict response and/ormonitor adherence to steroids as the dose increases throughout thecourse of treatment. This data may be combined with other informationgathered by the invention.

Other embodiments of the invention may be used to diagnose or identify aspecific asthma phenotype.

Other embodiments of the invention may be used to diagnose or identifythe presence or absence of eosinophilic airway inflammation.

Other embodiments of the invention may be used to determine thelikelihood of response to a biological therapy. Examples of biologicaltherapies include but is not limited to those targeting Th2 high or Th2Low inflammation. Specific examples include but is not limited to IL-13,IL-4, IL-5, IgE, TLR9, TSLP etc.

Other embodiments of the invention may use the collected information todetermine the level of disease control in one patient or a patientpopulation.

Other embodiments of the invention may be used to identify treatmentfailure on inhaled corticosteroids.

In another embodiment of the invention, the information gathered may beused to determine effectiveness of therapy or failure of therapy.Effectiveness may be determined by a drugs ability to keep one orseveral biomarkers at or below a baseline reading. Ineffectiveness orfailure of therapy may be determined by a biomarker measurement that isabove a baseline reading for a particular patient.

In one embodiment of the invention, the information gathered may be usedto determine proper inhaler technique. In this embodiment, a biomarkeror biomarkers may be used confirm deposition of the drug to the lung orpharmacodynamic effect.

In one embodiment, exhaled nitric oxide is used as a biomarker topredict response and monitor adherence and efficacy to inhaledcorticosteroids. This information may be combined with other datagathered by the invention.

Other embodiments use the data to generate data for pharmaceutical andmed tech research and development, identify patients for clinical trialsand communicate with patients and physicians for marketing purposes.

Patients may use implementations of the invention to view theinformation about the status and progression of their condition overtime and input information about themselves and find effective therapiesbased on the population in the database.

Under another embodiment of the invention, a trained medicalprofessional may work in combination with the system monitoring softwareto identify trends and proactively intervene before patients have healthproblems or consume expensive medical resources such as emergency roomvisits. FIG. 18 is an example of the type of information that iscollected from the patient.

FIG. 19 illustrates an illustrative implementation of the inventiongathering data [1901, 1902, 1903] from individual patients [1904, 1905,1906] in a mobile application [1907] and sending the data [1908] to aremote database [1909] where it may be analyzed and queried by payers,providers, patients and industry [1910].

FIG. 20 illustrates examples of different types of data gathered foreach patient either by manual or automatic collection. Biological data[2001] is gathered from a single patient [2011] at home, in thephysician office or in the pharmacy. Biomarkers, such as exhaled nitricoxide measurement from a breath test [2004] and periostin from blood[2005] and lung function i.e. spirometry [2006], may be collected from adevice attached to a computing device (i.e. phone, computer, tabletetc.) or the test result may be input manually. Collecting additionalbiomarkers is possible without deviating from the spirit of theinvention. Data collected regarding medical history and prescribedtherapy [2002] may be collected at home and/or the physician office andis overseen by the physician [2007]. This data may be input manually orpulled automatically from a medical record. Environmental and symptomdata [2003] is collected automatically and manually. Environmental data[2008] may include weather, air pollution, and/or allergen index.Location data may be provided by sensors inside of smart phones andoverlaid onto environmental data. Particulate matter may be synced by adevice with an embedded sensor located in the patients home. Symptomdata [2009] is gathered by querying the patient in between visits aboutthe frequency and severity of their symptoms and about the degree towhich the condition is impairing their daily life. All of thisinformation is sent to remote servers for storage and analysis [2010].

FIG. 21 illustrates a monitoring system for chronic respiratorydiseases. Data is collected and transmitted [2104] from patients [2102]in various methods as described in the invention. The information isstored remotely [2103] and monitored by a health professional [2101] asa service. The health professional is able to communicate [2105] to thepatients for a variety of reasons related to their health status.

FIG. 22 illustrates a software based monitoring system for chronicrespiratory diseases. Data collected and transmitted [2202] frompatients [2303] in various methods as described in the invention. Thedata is stored and monitored remotely [2205] and an alert system istriggered [2206] when the patients' information trends or passes beyonda predetermined threshold. When an alert is triggered, the medicalprofessional and/or caregiver [2201] and the individual patient [2208]may be alerted. The health professional and/or caregiver is able tocommunicate [2207] to the patients for a variety of reasons related totheir health status.

1.-144. (canceled)
 145. A test strip comprising: a flexible substratelayer; a first electrode pair disposed upon the flexible substratelayer; at least one sensing chemistry selected based on an analyte ofinterest, the sensing chemistry being disposed upon at least a portionof the substrate layer, and the sensing chemistry being disposed upon atleast a portion of the first electrode pair, wherein the sensingchemistry comprises functionalized nanostructures to bind to an analytecausing at least one of an electrical resistance change across thenanostructures and a redox reaction at the nanostructures; at least oneflexible spacing layer, the at least one flexible spacing layer disposedupon at least a portion of the flexible substrate layer, and the atleast one flexible spacing layer disposed upon at least a portion of thefirst electrode pair, and wherein the flexible spacing layer is not incontact with at least a portion of the sensing chemistry; and a flexibleprotective layer disposed above the flexible spacing layer, wherein theflexible protective layer is not in contact with at least a portion ofthe sensing chemistry, wherein the flexible protective layer isimpermeable to at least the analyte of interest; and wherein at least aportion of the flexible substrate layer, at least a portion of the atleast one flexible spacing layer, and at least a portion of the flexibleprotective layer define a chamber enclosing at least a portion of thefunctionalized nanostructures.
 146. The test strip of claim 145, whereinthe flexible protective layer is removable.
 147. The test strip of claim145, wherein the flexible protective layer is a foil layer.
 148. Thetest strip of claim 145, wherein the at least one sensing chemistrycomprises at least one of the following: an organic molecule having atleast one of an aromatic compound, an ionic functional group, a metal, ametal oxide, a metal salt, a metal-ligand complex, an organic dye, apolymer, and/or a heterocyclic macrocycle.
 149. The test strip of claim145, wherein one or more of the at least one flexible spacing layer andthe flexible protective layer is a membrane layer comprising at leastone of a composite material, a fibrous material, a woven textile, anon-woven textile, a polymer, an adhesive, a film, a gel, PTFE, andsilicone.
 150. The test strip of claim 145, wherein the at least onesensing chemistry comprises: an active sensing chemistry that issensitive to the analyte of interest in a sample and forming a firstnanonetwork in electrical communication with the first electrode pair;and a reference sensing chemistry that is sensitive to an analyte in thesample and forming a second nanonetwork in electrical communication witha second electrode pair.
 151. The test strip of claim 150, wherein theactive sensing chemistry and the reference sensing chemistry comprisethe same material.
 152. The test strip of claim 150, wherein thereference sensing chemistry is sensitive to a different set of analytesthan the active sensing chemistry.
 153. The test strip of claim 150,further comprising a circuit in cooperation with the active sensingchemistry and the reference sensing chemistry to form a bridge circuit.154. The test strip of claim 145, wherein the at least one sensingchemistry comprises: an active sensing chemistry responsive to theanalyte of interest in a sample and in electrical communication with thefirst electrode pair; a reference sensing chemistry responsive to ananalyte in the sample and in electrical communication with a secondelectrode pair; and at least one additional layer comprises a flexibleblocking layer disposed over the reference sensing chemistry, theflexible blocking layer for inhibiting contact between the referencesensing chemistry and at least one analyte in the sample.
 155. The teststrip of claim 145, further comprising a second flexible protectivelayer disposed upon the flexible spacing layer, wherein the secondflexible protective layer is not in contact with at least a portion ofthe sensing chemistry, and wherein the second flexible protective layeris permeable to at least the analyte of interest.
 156. The test strip ofclaim 155, wherein the at least one sensing chemistry comprises at leastone of the following: an organic molecule having at least one of anaromatic compound, an ionic functional group, a metal, a metal oxide, ametal salt, a metal-ligand complex, an organic dye, a polymer, and/or aheterocyclic macrocycle.
 157. The test strip of claim 155, wherein oneor more of the at least one flexible spacing layer and the secondflexible protective layer is a membrane layer comprising at least one ofa porous polymer, a non-porous polymer, a composite material, a fibrousmaterial, a woven textile, a non-woven textile, a polymer, an adhesive,a film, a gel, PTFE, and silicone.
 158. The test strip of claim 157,wherein the flexible protective layer is a membrane layer comprising atleast one of a composite material, a fibrous material, a woven textile,a non-woven textile, a polymer, an adhesive, a film, a gel, PTFE, andsilicone.
 159. The test strip of claim 157, wherein the membrane layeris permeable to at least the analyte of interest.
 160. The test strip ofclaim 155, wherein the at least one sensing chemistry comprises: anactive sensing chemistry that is sensitive to the analyte of interest ina sample and forming a first nanonetwork in electrical communicationwith the first electrode pair; and a reference sensing chemistry that issensitive to an analyte in the sample and forming a second nanonetworkin electrical communication with a second electrode pair.
 161. The teststrip of claim 160, wherein the active sensing chemistry and thereference sensing chemistry comprise the same material.
 162. The teststrip of claim 160, wherein the reference sensing chemistry is sensitiveto a different set of analytes than the active sensing chemistry. 163.The test strip of claim 160, further comprising a circuit in cooperationwith the active sensing chemistry and the reference sensing chemistry toform a bridge circuit.
 164. The test strip of claim 155, wherein the atleast one sensing chemistry comprises: an active sensing chemistryresponsive to the analyte of interest in a sample and in electricalcommunication with the first electrode pair; a reference sensingchemistry responsive to an analyte in the sample and in electricalcommunication with a second electrode pair; and at least one additionallayer comprises a flexible blocking layer disposed over the referencesensing chemistry, the flexible blocking layer for inhibiting contactbetween the reference sensing chemistry and at least one analyte in thesample.
 165. The test strip of claim 155, wherein the permeability ofthe second flexible protective layer is provided by at least one window.166. A method for determining a concentration of at least one analyte ina fluid sample, the method comprising: providing a test stripcomprising: a flexible substrate layer; a first electrode pair disposedupon the flexible substrate layer; at least one sensing chemistryselected based on an analyte of interest, the sensing chemistry beingdisposed upon at least a portion of the substrate layer, and the sensingchemistry being disposed upon at least a portion of the electrode pair,wherein the sensing chemistry comprises functionalized nanostructures tobind to an analyte causing at least one of an electrical resistancechange across the nanostructures and a redox reaction at thenanostructures; at least one flexible spacing layer, the at least oneflexible spacing layer disposed upon at least a portion of the flexiblesubstrate layer, and the at least one flexible spacing layer disposedupon at least a portion of the first electrode pair, and wherein theflexible spacing layer is not in contact with at least a portion of thesensing chemistry; and a flexible protective layer disposed above theflexible spacing layer, wherein the flexible protective layer is not incontact with at least a portion of the sensing chemistry, wherein theflexible protective layer is impermeable to at least the analyte ofinterest; and wherein at least a portion of the flexible substratelayer, at least a portion of the at least one flexible spacing layer,and at least a portion of the flexible protective layer define a chamberenclosing at least a portion of the functionalized nanostructures; andmeasuring at least one of an electrical resistance change across thenanostructures and a redox reaction at the nanostructures via the firstelectrode pair.
 167. The test strip of claim 166, wherein the flexibleprotective layer is removable.
 168. The method of claim 166, wherein theflexible protective layer is a foil layer.
 169. The method of claim 166,wherein one or more of the at least one flexible spacing layer and theflexible protective layer is a membrane layer comprising at least one ofa composite material, a fibrous material, a woven textile, a non-woventextile, a polymer, an adhesive, a film, a gel, PTFE, and silicone. 170.The method of claim 166, wherein the at least one sensing chemistrycomprises: an active sensing chemistry that is sensitive to the analyteof interest in a sample and forming a first nanonetwork in electricalcommunication with the first electrode pair; and a reference sensingchemistry that is sensitive to an analyte in the sample and forming asecond nanonetwork in electrical communication with a second electrodepair.
 171. The method of claim 168, wherein the active sensing chemistryand the reference sensing chemistry comprise the same material.
 172. Themethod of claim 168, wherein the reference sensing chemistry issensitive to a different set of analytes than the active sensingchemistry.
 173. The method of claim 166, wherein the at least onesensing chemistry comprises: an active sensing chemistry responsive tothe analyte of interest in a sample and in electrical communication withthe first electrode pair; a reference sensing chemistry responsive to ananalyte in the sample and in electrical communication with a secondelectrode pair; at least one additional layer comprises a flexibleblocking layer disposed over the reference sensing chemistry, theflexible blocking layer for inhibiting contact between the referencesensing chemistry and at least one analyte in the sample; and whereinthe method further comprises measuring at least one of an electricalresistance change across the nanostructures and a redox reaction at thenanostructures via the second electrode pair.
 174. The method of claim166, further comprising providing the fluid sample, and wherein the atleast one analyte is gaseous and at least one of nitric oxide, hydrogen,and methane.
 175. The method of claim 166, wherein the test stripfurther comprises a second flexible protective layer disposed upon theflexible spacing layer, wherein the second flexible protective layer isnot in contact with at least a portion of the sensing chemistry, andwherein the second flexible protective layer is permeable to at leastthe analyte of interest.
 176. The method of claim 175, wherein one ormore of the at least one flexible spacing layer and the second flexibleprotective layer is a membrane layer comprising at least one of a porouspolymer, a non-porous polymer, a composite material, a fibrous material,a woven textile, a non-woven textile, a polymer, an adhesive, a film, agel, PTFE, and silicone.
 177. The test strip of claim 176, wherein theflexible protective layer is a membrane layer comprising at least one ofa composite material, a fibrous material, a woven textile, a non-woventextile, a polymer, an adhesive, a film, a gel, PTFE, and silicone. 178.The method of claim 177, wherein the membrane layer is selectivelypermeable to at least the analyte of interest.
 179. The method of claim175, wherein the at least one sensing chemistry comprises: an activesensing chemistry that is sensitive to the analyte of interest in asample and forming a first nanonetwork in electrical communication withthe first electrode pair; and a reference sensing chemistry that issensitive to an analyte in the sample and forming a second nanonetworkin electrical communication with a second electrode pair.
 180. Themethod of claim 179, wherein the active sensing chemistry and thereference sensing chemistry comprise the same material.
 181. The methodof claim 179, wherein the reference sensing chemistry is sensitive to adifferent set of analytes than the active sensing chemistry.
 182. Themethod of claim 175, wherein the at least one sensing chemistrycomprises: an active sensing chemistry responsive to the analyte ofinterest in a sample and in electrical communication with the firstelectrode pair; a reference sensing chemistry responsive to an analytein the sample and in electrical communication with a second electrodepair; at least one additional layer comprises a flexible blocking layerdisposed over the reference sensing chemistry, the flexible blockinglayer for inhibiting contact between the reference sensing chemistry andat least one analyte in the sample; and wherein the method furthercomprises measuring at least one of an electrical resistance changeacross the nanostructures and a redox reaction at the nanostructures viathe second electrode pair.
 183. The method of claim 175, furthercomprising providing the fluid sample, and wherein the at least oneanalyte is gaseous and at least one of nitric oxide, hydrogen, andmethane.